Discovery of the widespread and impressive properties of fluoroimidazoles as biological substrates and analogs has provided the impetus for the synthesis of other substituted imidazoles. Methods for their synthesis, however, were largely unknown and our explorations of resonance and inductive effects in imidazoles provided the basis for development of new synthetic methods. Thus, intermediates for the synthesis of 2,4-difluoroimidazoles have become available for the first time. Development of the triphenylmethyl blocking group for imidazole nitrogen provided the first general route to 2-substituted imidazoles (including histamines and histidines). A novel route to 2-trifluoromethyl-imidazoles (including histidine and histamine) has been discovered, based on the reaction of non-cyclic precursors with trifluoroacetic anhydride. These analogs will be very useful in evaluating the significance of an acidic ring NH on the biological properties of the natural imidazoles. BIBLIOGRAPHIC REFERENCES: Y. Kikugawa and L.A. Cohen: Synthesis of N-alkylimidazoles from N-alkyloxazolium salts. Chem. Pharm. Bull., 24, 3205-3207 (1976). Takeuchi, Y., Cohen, P.A., Kirk, K.L., and Cohen, L.A.: Mechanisms for Hydrogen-Deuterium Exchange in Ring-fluorinated Imidazoles. Abstracts, 1977 Annual Meeting, American Chemical Society, in press.